This competitive renewal application is to continue on going studies in mice aimed at our long held goal of generating knowledge that can be used to mitigate, and remediate, alveolar loss in individuals with chronic obstructive pulmonary disease (COPD). In spite of 50 years of intensive research, it was recently pointed out that therapies for COPD are inadequate, and none slow the relentless progression of the disease. We think this application takes a different approach from most past research on COPD. We use the mouse model of calorie restriction related alveolar loss and refeeding induced alveolar regeneration. Our enthusiasm for this model is because it is one of a very few conserved from rodents to humans. Specific aim 1 continues our hypothesis generated search for reagents that induce regenerative alveologenesis. Specific aim 1a tests the hypothesis that signaling via epidermal growth factor receptor induces alveolar regeneration and increases lung tissue recoil in mice with elastase induced emphysema. It is supported by 1) protein level confirmation of microarray measured global gene expression in lung and 2) the demonstration in several laboratories that pharmacological agents can induce remediation of elastase and cigarette induced emphysema in young adult and aged rodents, We continue informed and noninformed analysis of already measured global gene expression to generate data from which hypotheses have been, and will continue to be, formed (Specific aim 1b). Use of global gene expression is required because of the paucity of information that allows hypothesis formation regarding regenerative alveologenesis, and the evidence that gene expression determinative of developmental and regenerative alveologenesis are different. Cachexia in people with COPD signals a rapid downhill course. Adiponectin, a "starvation signal," is elevated in the plasma of individuals with COPD, and in lungs of calorie restricted mice. Therefore, we will test the hypothesis this "starvation signal" induces alveolar loss in ad libitum fed mice with elastase induced emphysema (Specific aim 2). Specific aim 3 tests the hypothesis that attempts to mitigate and remediate alveolar loss in COPD must consider conditions as they are in the alveoli of people with COPD, e.g., hypoxia, inflammation (which may be caused by hypoxia), decreased perfusion and inadequate delivery of nutrients. Our hypothesis is that hypoxia, i.e., 17% O2 concentration, as exists in Denver, will impair remediation of elastase induced emphysema by all-trans retinoic acid, and will accelerate the loss of alveoli and lung tissue recoil in untreated mice with elastase induce emphysema. Two observations support specific aim 3: 1) alveologenesis is impaired by hypoxia, and 2) in the inland western US, several states (Idaho, Wyoming, Colorado, New Mexico, and Arizona) exhibit a puzzling disparity between smoking attributable mortality, and the much higher mortality from COPD. The average altitude of these states is above 4000 ft. We think the proposed experiments will provide much needed new insights into the mitigation and remediation of COPD. PUBLIC HEALTH RELEVANCE. Chronic obstructive pulmonary disease (COPD) is the 5th most common cause of death in industrialized nations, and is predicted to rise to 3rd most common by 2020. There is not treatment that slows the relentless progression of the disease or that reverses it. In this application, we use an animal model to investigate methods to slow progression and reverse the disease.